Background: Coronary artery disease (CAD) is the leading cause of mortality in the USA accounting for 40% of all deaths. A broad spectrum of biochemical and genetic factors are currently emerging as potential markers and/or causal agents of atherothrombotic vascular disease. The genetic influences involve many pathways including the coagulation and inflammatory pathways, lipoprotein metabolism, and factors that maintain vascular tone. In one study, we examined the ACE I/D polymorphism.1) The deletion allele of the I/D polymorphism in the angiotensin converting enzyme (ACE) gene has been associated with increased incidence of cardiovascular pathology. The risk is synergistically increased in patients who also possess the C allele at position 1166 of the angiotensin type I (AT1) receptor gene. Since abnormal coronary vasomotion contributes to the pathogenesis of vascular disease, we investigated whether these polymorphisms modulate vasomotor tone and regulate endothelial function. Methods and Results: In 177 patients with coronary atherosclerosis or its risk factors, we investigated endothelial function with intracoronary acetylcholine (ACH),endothelium- independent smooth muscle function with sodium nitroprusside (SNP), and basal nitric oxide (NO) activity with L-NG monomethyl arginine (L-NMMA). Compared to II genotype, patients with the DD genotype had lower coronary microvascular and epicardial responses with SNP. The presence of the D allele was an independent predictor of the response to SNP on multivariate analysis. L-NMMA induced greater constriction in patients with the DD compared to II genotype. Intermediate responses were observed in the heterozygotes. No difference in ACH-mediated vasomotion was detected between the three ACE genotypes. The AT1 receptor polymorphism did not influence responses to either SNP or ACH.Conclusions: Patients possessing the D allele of the ACE gene haveincreased vascular smooth muscle tone. The enhanced tone appears to be counter-balanced by an increase in basal NO activity in patients with atherosclerosis. In contrast, the AT1 receptor A/C polymorphism is not a determinant of coronary vasomotor function and does not modulate the effects of the ACE genotype on the vascular phenotype.We are currently studying the impact of several other polymorphisms on vascular function. - Vascular function, genetics, acetylcholine, atherosclerosis, nitric oxide - Human Subjects